1-155066845-A-G

Variant names:

• chr1-155066845-A-G
• rs138277393
• NM_005227.3:c.229A>G
• EFNA4 p.Met77Val

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PVS1_ModerateBS2

The NM_001406810.1(EFNA4):c.1A>G (p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. Note: NM_001406810.1 is not a MANE Select or MANE Plus Clinical transcript for EFNA4; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant disrupts the start codon, preventing normal translation initiation. The variant allele was found at a cumulative frequency of 0.0000291 (AC=47) in the gnomAD database across 1,613,898 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00032. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: EFNA4 NM_001406810.1 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08
• Publications: 0 publications found

Genes affected

EFNA4 (HGNC:3224): (ephrin A4) This gene encodes a member of the ephrin (EPH) family. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, especially in the nervous system and in erythropoiesis. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. This gene encodes an EFNA class ephrin that has been implicated in proliferation and metastasis of several types of cancers. [provided by RefSeq, May 2022]

EFNA4 Gene-Disease associations (from GenCC):

• craniosynostosis

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

EFNA4-EFNA3 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Likely_benign. The variant received -2 points.

• PVS1: Start-lost with downstream start: >10% CDS truncated — moderate (PVS1 downgraded to PM); Start codon lost (exon 3 of 5); downstream rescue start codon present, but it truncates more than 10% of the CDS.
• BS2: Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 0.; Cumulative gnomAD AC = 47 (pure AD gene, not AR).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001406810.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFNA4	NM_005227.3	MANE Select	c.229A>G	p.Met77Val	missense	Exon 2 of 4	NP_005218.1	P52798-1
	EFNA4	NM_001406810.1		c.1A>G	p.Met1?	start_lost	Exon 3 of 5	NP_001393739.1
	EFNA4	NM_182689.2		c.229A>G	p.Met77Val	missense	Exon 2 of 4	NP_872631.1	P52798-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFNA4	ENST00000368409.8	TSL:1 MANE Select	c.229A>G	p.Met77Val	missense	Exon 2 of 4	ENSP00000357394.3	P52798-1
	EFNA4	ENST00000359751.8	TSL:1	c.229A>G	p.Met77Val	missense	Exon 2 of 4	ENSP00000352789.4	P52798-2
	EFNA4-EFNA3	ENST00000505139.1	TSL:2	c.113+2909A>G		intron	N/A	ENSP00000426741.1	K9J7H7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	0.000138	21	0	152192	32
GnomAD2 exomes	0.0000757	19		250970
GnomAD4 exome	0.0000178	26	0	1461706	32
GnomAD4 genome	0.000138	21	0	152192	32
TOPMed (Bravo)	0.000117
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.000111	4	0	36010
Local & regional cohorts 1 source Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	0.0000769	1		13006

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000884	10	113084	0.0000578	11	190474

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	22
AlphaMissense	Benign	-	0.29
BayesDel_addAF	Benign	T	-0.12
BayesDel_noAF	Uncertain	-	-0.040
CADD	Benign	-	20
DANN	Uncertain	-	0.98
DEOGEN2	Pathogenic	D	0.85
Eigen	Benign	-	0.047
Eigen_PC	Benign	-	0.13
FATHMM_MKL	Uncertain	D	0.97
FuncVEP CTI	Benign	-	0.010
GPN-Star LLR	N/A	-	-4.3
GPN-Star score	N/A	-	4.3
LIST_S2	Benign	T	0.60
M_CAP	Uncertain	D	0.13
MetaRNN	Benign	T	0.23
MetaSVM	Uncertain	D	0.34
Mutation Taster	N/A	polymorphism	90/10
MutationAssessor	Uncertain	M	2.5
PhyloP100	Uncertain	-	4.1
popEVE	Benign	-	-3.6
PROVEAN	Uncertain	D	-3.4
RBP_binding_hub_radar	N/A	-	0.0
RBP_regulation_power_radar	N/A	-	1.7
REVEL	Uncertain	-	0.53
Sift	Uncertain	D	0.019
Sift4G	Uncertain	D	0.045
Varity_R	N/A	-	0.27
VESM-3B	Benign	-	-8.0

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.040
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.080

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs138277393;

hg19: chr1-155039321;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar